Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics
Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to contro...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Psychiatry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1182535/full |
| _version_ | 1797692569781534720 |
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| author | Albert Stuart Reece Albert Stuart Reece Gary Kenneth Hulse Gary Kenneth Hulse |
| author_facet | Albert Stuart Reece Albert Stuart Reece Gary Kenneth Hulse Gary Kenneth Hulse |
| author_sort | Albert Stuart Reece |
| collection | DOAJ |
| description | Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration. |
| first_indexed | 2024-03-12T02:30:30Z |
| format | Article |
| id | doaj.art-fdd5ca5d409446bf95179169204c13fd |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-03-12T02:30:30Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-fdd5ca5d409446bf95179169204c13fd2023-09-05T09:04:45ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-09-011410.3389/fpsyt.2023.11825351182535Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomicsAlbert Stuart Reece0Albert Stuart Reece1Gary Kenneth Hulse2Gary Kenneth Hulse3Division of Psychiatry, University of Western Australia, Crawley, WA, AustraliaSchool of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, AustraliaDivision of Psychiatry, University of Western Australia, Crawley, WA, AustraliaSchool of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, AustraliaMuch recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1182535/fullcannabiscannabinoidgenotoxicityepigenotoxicitytransgenerational inheritance |
| spellingShingle | Albert Stuart Reece Albert Stuart Reece Gary Kenneth Hulse Gary Kenneth Hulse Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics Frontiers in Psychiatry cannabis cannabinoid genotoxicity epigenotoxicity transgenerational inheritance |
| title | Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics |
| title_full | Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics |
| title_fullStr | Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics |
| title_full_unstemmed | Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics |
| title_short | Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics |
| title_sort | perturbation of 3d nuclear architecture epigenomic dysregulation and aging and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology part 1 aging and epigenomics |
| topic | cannabis cannabinoid genotoxicity epigenotoxicity transgenerational inheritance |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1182535/full |
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